The proposed research continues previously funded studies on the pathophysiology of psychotic major depression (PMD), a severe and often debilitating form of depression. Results thus far indicate that PMD patients have increased and phase advanced corticotropin (ACTH) circadian rhythms, increased overnight cortisol levels, and prefrontal cognitive deficits that may originate in glucocorticoid (GC) effects on ascending mesocortical dopamine (DA) pathways. Parallel studies in animals indicate that chronic administration of GC's decreases DA utilization in rat prefrontal cortex, and impairs prefrontal DA mediated cognitive performance in squirrel monkeys. Moreover, GC receptor blockade by mifepristone produces rapid relief of PMD cognitive impairments as measured by psychiatric tests. Based on these results, the proposed studies test the following four hypotheses: (l) Hypothalamic-pituitary-adrenal (HPA) axis dysregulation in PMD is associated with specific cognitive impairments in executive functions, attention, and semantic analysis, and with correlated volumetric losses and functional activation abnormalities in prefrontal cortex and the hippocampal formation, as measured by structural and functional magnetic resonance imaging (fMRI); (2) Mifepristone treatment relieves PMD cognitive deficits and delusional symptoms as measured by psychometric and psychiatric tests, normalizes the PMD phase advance in plasma ACTH circadian rhythms, and is accompanied by functional reorganizations in prefrontal cortical networks as measured by fMRI; (3) In monkeys, chronic stress induces prefrontal cognitive impairments analogous to those seen previously with chronic UC treatment, and these stress effects are blocked by mifepristone; and (4) In rats, mifepristone blocks the effects of chronic stress and chronic GC treatment on prefrontal DA metabolism. The approaches used to address these aims move across the boundaries of clinical psychopharmacology, basic behavioral neuroscience, experimental neurochemistry, and functional neuroimaging, with the ultimate goal of understanding why some depressed patients become psychotic or otherwise cognitively impaired, and uncovering new and faster methods of treatment for PMD and related psychotic disorders.